Within the field of pharmaceutical sciences, specialized dosage forms providing an extended duration of drug action are classified into several groups. While such formulations all share the common objective of prolonging the length of drug activity in the body, they may achieve this in various ways. The various subgroups include extended-, sustained-, delayed- and pulsed-release formulations. A controlled release profile can be obtained by chemical modification of the drug compound (i.e. salts, esters, complexes), by the use off pharmaceutical excipients, by varying formulation parameters (i.e. particle size, tablet hardness), as well as by the individual selection of the route and means of application.
The application of therapeutic drug compounds to the lung is especially challenging, as the organ's high sensitivity restricts the number of excipients suitable for pulmonary delivery and, further, a controlled, reproducible release in the lung is difficult to achieve. Liposomes are considered to be formulations with a high tolerance and little to no toxicity. This claim is based upon the excellent biocompatibility trackrecord established by several approved liposomal formulations already on the market, including the products Daunoxome®, Ambisome®, and HeparinPur® Liposomal formulations are thought to be especially suitable for application in the lung, as they can be prepared partially or wholly from natural substances endogenous to the lung.
The pharmaceutical term “liposomes” describes a drug delivery vehicle comprised of lipid vesicles, which exhibit a strong structural resemblance to cellular membranes. In the same manner as a cellular membrane, the liposomal vesicles walls (composed often of a phospholipid bilayer) are able to divide an internal aqueous compartment from the external aqueous medium. Liposomes can form spontaneously according to the laws of thermodynamics when, for example, a small amount of phospholipids is dispersed in a larger volume of an aqueous medium. Liposomes are generally prepared from natural, partially synthetic, and synthetic phospholipids. Although other lipids exhibit a cone-shaped molecular structure, which favors micelle formation, phospholipids favor the formation of lamellar structures, due to their cylindrical geometry resulting from the two fatty acid chains of the phopholipid molecule.
The structure of individual liposomal lamellae is similar to that of a cellular membrane. The phospholipids form a bi-layer, within which the hydrophobic portions of the molecule extend inwards and the hydrophilic groups interact with the external and internal aqueous phase.
According to their structure and size, liposomes can be divided into several groups (Table 1).
TABLE 1ClassificationDiameterStructureMLV100-5000 nmmultiple bilayers(multilamellarvesicles)SUV<100 nmsmall, unilamellar(small, unilamellar(up to 2000 nm)vesicles with a hy-vesicles)drophilic internalcompartmentLUV>100 nmlarge, unilamellar(large, unilamellarvesicles with a hy-vesicles)drophilic internalcompartment
Due to the coexistence of both hydrophilic and hydrophobic regions within liposomes, drug compounds can be incorporated in different ways. Lipophilic compounds accumulate primarily within the lipid bilayer, whereas hydrophilic compounds are generally found either in the aqueous layers between the vesicle bilayer walls or in the aqueous internal compartment. Amphiphilic compounds insert themselves between the phospholipids along the phase interface. The properties of the different liposomal classes determine their applicability. For example, the high amount of lipids found in SUVs make them suitable carriers for lipophilic substances, whereas the large volume of the LUV aqueous internal compartment can hold a high amount of hydrophilic compounds. A sustained release of drug compounds from the liposomal structures is achieved most efficiently with a MLV structure, which requires the compound to cross several diffusion barriers (lipid bilayers) before release.
Both the excellent biocompatibility, as well as the possibility of modifying the pharmacokinetic profile (i.e. through sustained-release formulations) make liposomes a promising vehicle for the controlled and sustained release of drug compounds in the lung.
The development of a formulation based on liposomes for the controlled and sustained release of drug compounds in the lung could be highly relevant for the successful therapy of many diseases. The treatment of lung diseases may especially benefit from the possibility of delivering therapeutic drugs directly to the target organ and, once there, the establishment of a high local drug concentration with a prolonged drug activity at the the site of action. Further, a sustained drug release can lead to a decrease in the number and intensity of side effects by avoiding fluctuations in the drug concentration, as well as concentration peaks immediately after application. Drug encapsulation within liposomes can also protect compounds with a short biological half-life from inactivation before release. In contrast, the encapsulation of compounds with a long biological half-life, such as those used for the treatment of asthma or chronic obstructive pulmonary disease (COPD), may prevent the compound from crossing the air-blood barrier into the systemic circulation and causing systemic side effects. In addition to the previously mentioned lung disorders, asthma and COPD, such lung diseases as pneumonia and pulmonary hypertension are representative of conditions that could be better treated with liposomal drug formulations. For example, the current form of therapy for pulmonary hypertension is based upon the inhalation of vasodilators (i.e. prostacyclin and derivatives thereof). The short biological half-life of these compounds results in the need for frequent sometimes even hourly inhalations, each with a duration of approximately 15 minutes, to achieve a continual, effective pressure reduction in the pulmonary circulation. A sustained-release liposomal formulation for these substances could drastically reduce the frequency of inhalation and guarantee a constant therapeutic reduction in the pulmonary pressure. Both factors would greatly improve patient quality of life.
In addition to the local application of liposomes to treat lung diseases, a controlled and sustained release of drug compounds in the lung may also be of interest for systemic disorders, such as diabetes mellitus. The lung is an organ, which due to its extremely thin air-blood barrier, as well as its large alveolar surface area, has a high capability to absorb drug compounds and allow them to pass into the systemic circulation. For this reason, drug compounds may be applied to the lung for transpulmonary delivery to treat systemic disorders. For example, an aerosolized form of insulin for pulmonary application is currently being developed as an alternative to the subcutaneous insulin injection. However, none of the formulations to date are able to achieve a continual basal insulin release into the circulation.
As of yet, no depot formulation for the pulmonary application of drug compounds has been successfully developed. Currently, the only possibility to achieve a long drug activity in the lung is to apply compounds with adequently long halflives.
The standard method of applying drug compounds to the lung is the inhalation of aerosols. Aerosols containing drug substances can be generated by various methods. The most common devices include air-jet and ultrasonic nebulizers, although metered-dose inhalers and dry powder inhalers are also used. The deposition of the aerosol in the respiratory tract is highly dependent upon particle size distribution of the aerosol droplets. A high percent of particles with an aerodynamic diameter smaller than 6 μm usually reach the trachea, bronchial region, and alveolar space. As a result, only aerosols with aerodynamic diameters smaller than 6 μm should be used for therapeutic purposes.
Drug formulations in aqueous solutions can be aerosolized with air-jet and ultrasonic nebulizers. Metered-dose inhalers and dry powder inhalers require additional formulation modifications (i.e. the solubilization or suspension of the drug in a propellant, micronization of the drug). The aerosolization of aqueous liposomal dispersions can be achieved by air-jet or ultrasonic nebulization. Common to both methods of nebulization is the principle that small aerosol droplets are generated from a liquid reservior by the application of mechanical energy to the system. The generated aerosol droplets and the liposomal vesicles within them are subjected to aggressive forces which may compromise liposome integrity leading to a premature release of the vesicle contents. Therefore, a sufficient stability of the aerosolized liposome depot formulation is a primary requirement for pulmonary application. The stability of liposomes during nebulization is dependent upon several factors, including technical parameters of the nebulization process (i.e. pressure, ultrasonic frequency) and especially liposome characteristics, such as size, type, and the chemical structure of the lipid components. Another method to administer drug compounds to the lung is an intratracheal instillation. This process involves the insertion of a tube into the trachea or the bronchial region and allowing the drug solution to flow via the tube into the lung. Although this method of application does not require the high stability standards for liposomal formulations as compared to aerosolization, the instillation of a fluid leads to an inhomogeous distribution of the drug solution within the lung. Further, the invasive nature of this application method severely limits its practical use and it cannot be considered suitable for out-patient or long-term treatment. To be considered suitable as a depot formulation for the respiratory tract, a liposomal formulation must possess a sufficient stability during the nebulization process, be able to be incorporated within aerosol droplets smaller than 6 μm, and guarantee a controlled, sustained release of the drug substance at the targeted site of action. The release of the drug substance should ideally begin immediately after deposition of the liposomes in the lung and continue over a period of several hours.